Summary/Abstract Pain is a national health challenge costing our economy more than $600 Billions per year. Faced with ineffective therapies, millions of patients are being over-prescribed opioid-based medications, which is contributing to addiction and lethal overdose. This application is in response to RFA-NS-18-009 ?BRAIN Initiative: Targeted BRAIN Circuits Projects (R01)? which calls for ?Innovative approaches and new paradigms for identifying and understanding nociception and pain in the context of circuit mechanisms of the central nervous system?. We propose AIM 1) tool development to test the hypothesis that Laminae II/III PV neurons inhibit nociceptive relay neurons in vivo, AIM 2) behavioral development to validate a novel model for rapid reporting of sensory stimuli, and AIM 3) combination of real-time neural recording from the spine-brain continuum and ecological behavior to test the hypothesis that distinct rhythms in sensory thalamus and neocortex are temporally correlated with tactile and noxious stimuli. Moreover, excitation of PV neurons inhibits thalamic neurons and modulates thalamocortical rhythms. These aims will be investigated using laboratory animal models of pain and state-of-the-art techniques for simultaneous recording from multiple areas in the spine cord and brain, combined with cell-speci?c stimulation in the periphery using optical methods in awake rodents. Therefore, this application will enhance our scienti?c understanding of pain mechanisms in the central nervous system and potentially lead to novel diagnostic and therapeutic approaches.